Type 2 diabetes mellitus is a common chronic disease that develops in most populations in late middle age. The Pima Indians of Arizona have a very high prevalence of this disease, and in contrast to many populations, the disease often presents at an earlier age. As a result of the long-term epidemiologic studies, the familial nature of the disease has been well-documented, and segregation analysis suggests the possibility of a single major gene affecting age of onset. Genetic determinants of type 2 diabetes mellitus, its risk factors and its complications are being sought using techniques of genetic linkage analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained during the epidemiologic studies. An autosomal genome-wide linkage study, using 516 genetic markers, has been completed for 1338 individuals in 112pedigrees potentially informative for linkage studies of diabetes. The results of these analyses identified strong evidence for a gene influencing both obesity and diabetes on chromosome 11 and evidence for additional diabetes-susceptibility genes on chromosomes 1 and 7. In addition, potential genes influencing susceptibility to diabetic nephropathy were identified on chromosomes 7, and 18. Strong evidence for a locus on chromosome 19 influencing serum cholesterol concentrations was also found. Efforts at extending these findings through genotyping individuals in additional pedigrees and through fine-mapping are now underway. Methods to assess parent-of-origin effects in linkage analysis have also been developed.